Lysophosphatidylcholine Promoting α-Synuclein Aggregation in Parkinson's Disease: Disrupting GCase Glycosylation and Lysosomal α-Synuclein Degradation

Overview

Journal NPJ Parkinsons Dis

Date 2025 Mar 16

PMID 40089519

Authors

Chunyan Mu

Kaiquan Shao

Mingyu Su

Yurong Guo

Yuxiang Qiu

Ruiao Sun

Sihan Sun

Yaoyu Sun

Chenkai Liu

Wei Wang

Xiaoling Qin

Chuanxi Tang

Affiliations

Soon will be listed here.

Abstract

In Parkinson's Disease (PD), elevated serum lysophosphatidylcholine (LPC) levels correlate with disease progression. However, the mechanisms by which abnormal LPC elevation contributes to PD-related neurotoxicity remain poorly understood. This study aims to investigate the pathogenic role of LPC in dopaminergic neuronal damage and elucidates its underlying mechanisms. Our results showed LPC induces α-synuclein aggregation, exacerbating cognitive dysfunction. LPC activates Cleaved-Caspase3 via the orphan receptor GPR35-ERK signaling pathway, inhibits GRASP65 expression, and disrupts the polarized structure of the Golgi apparatus. This disruption impairs glycosylation and function of glucocerebrosidase (GCase), preventing its transport to lysosomes and leading to glucosylceramide (GlcCer) accumulation, a scaffold for α-synuclein aggregation. LPC also disrupts the autophagolysosomal pathway and lysosomal acidification, exacerbating toxic α-synuclein accumulation. Restoring GCase glycosylation, limiting GlcCer synthesis, or blocking ERK signaling mitigates these effects. This study highlights LPC's role in promoting α-synuclein aggregation and autophagolysosomal dysfunction, advancing our understanding of PD pathology.

References

Halli-Tierney A, Luker J, Carroll D . Parkinson Disease. Am Fam Physician. 2020; 102(11):679-691. View

Jankovic J . Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008; 79(4):368-76. DOI: 10.1136/jnnp.2007.131045. View

Ryan T, Caine J, Mertens H, Kirby N, Nigro J, Breheney K . Ammonium hydroxide treatment of Aβ produces an aggregate free solution suitable for biophysical and cell culture characterization. PeerJ. 2013; 1:e73. PMC: 3646356. DOI: 10.7717/peerj.73. View

Zheng Z, Zhu Z, Zhou C, Cao L, Zhao G . Burden of Parkinson Disease in China, 1990-2019: Findings from the 2019 Global Burden of Disease Study. Neuroepidemiology. 2022; 57(1):51-64. PMC: 10064393. DOI: 10.1159/000527372. View

Qi S, Yin P, Wang L, Qu M, Kan G, Zhang H . Prevalence of Parkinson's Disease: A Community-Based Study in China. Mov Disord. 2021; 36(12):2940-2944. DOI: 10.1002/mds.28762. View

Tian Y, Tang C, Wu J, Zhou J . Parkinson's disease in China. Neurol Sci. 2010; 32(1):23-30. DOI: 10.1007/s10072-010-0461-8. View

Liu P, Zhu W, Chen C, Yan B, Zhu L, Chen X . The mechanisms of lysophosphatidylcholine in the development of diseases. Life Sci. 2020; 247:117443. DOI: 10.1016/j.lfs.2020.117443. View

Sevastou I, Kaffe E, Mouratis M, Aidinis V . Lysoglycerophospholipids in chronic inflammatory disorders: the PLA(2)/LPC and ATX/LPA axes. Biochim Biophys Acta. 2012; 1831(1):42-60. DOI: 10.1016/j.bbalip.2012.07.019. View

Chen Y, Wen S, Jiang M, Zhu Y, Ding L, Shi H . Atherosclerotic dyslipidemia revealed by plasma lipidomics on ApoE mice fed a high-fat diet. Atherosclerosis. 2017; 262:78-86. DOI: 10.1016/j.atherosclerosis.2017.05.010. View

10.

Galper J, Mori G, McDonald G, Ahmadi Rastegar D, Pickford R, Lewis S . Prediction of motor and non-motor Parkinson's disease symptoms using serum lipidomics and machine learning: a 2-year study. NPJ Parkinsons Dis. 2024; 10(1):123. PMC: 11199659. DOI: 10.1038/s41531-024-00741-y. View

11.

Obis E, Sol J, Andres-Benito P, Martin-Gari M, Mota-Martorell N, Galo-Licona J . Lipidomic Alterations in the Cerebral Cortex and White Matter in Sporadic Alzheimer's Disease. Aging Dis. 2023; 14(5):1887-1916. PMC: 10529741. DOI: 10.14336/AD.2023.0217. View

12.

Muramatsu R, Kuroda M, Matoba K, Lin H, Takahashi C, Koyama Y . Prostacyclin prevents pericyte loss and demyelination induced by lysophosphatidylcholine in the central nervous system. J Biol Chem. 2015; 290(18):11515-25. PMC: 4416855. DOI: 10.1074/jbc.M114.587253. View

13.

Tian C, Li S, He L, Han X, Tang F, Huang R . Transient receptor potential ankyrin 1 contributes to the lysophosphatidylcholine-induced oxidative stress and cytotoxicity in OLN-93 oligodendrocyte. Cell Stress Chaperones. 2020; 25(6):955-968. PMC: 7591684. DOI: 10.1007/s12192-020-01131-y. View

14.

Sheikh A, Nagai A, Ryu J, McLarnon J, Kim S, Masuda J . Lysophosphatidylcholine induces glial cell activation: role of rho kinase. Glia. 2008; 57(8):898-907. DOI: 10.1002/glia.20815. View

15.

Fernandes Gomes B, Farris C, Ma Y, Concha-Marambio L, Lebovitz R, Nellgard B . α-Synuclein seed amplification assay as a diagnostic tool for parkinsonian disorders. Parkinsonism Relat Disord. 2023; 117:105807. DOI: 10.1016/j.parkreldis.2023.105807. View

16.

Kalsoom I, Wang Y, Li B, Wen H . Research Progress of α-Synuclein Aggregation Inhibitors for Potential Parkinson's Disease Treatment. Mini Rev Med Chem. 2023; 23(20):1959-1974. DOI: 10.2174/1389557523666230517163501. View

17.

Bodles A, Irvine G . Alpha-synuclein aggregation. Protein Pept Lett. 2004; 11(3):271-9. DOI: 10.2174/0929866043407084. View

18.

Kachappilly N, Srivastava J, Swain B, Thakur P . Interaction of alpha-synuclein with lipids. Methods Cell Biol. 2022; 169:43-66. DOI: 10.1016/bs.mcb.2021.12.002. View

19.

Vekrellis K, Rideout H, Stefanis L . Neurobiology of alpha-synuclein. Mol Neurobiol. 2004; 30(1):1-21. DOI: 10.1385/MN:30:1:001. View

20.

Duda J, Lee V, Trojanowski J . Neuropathology of synuclein aggregates. J Neurosci Res. 2000; 61(2):121-7. DOI: 10.1002/1097-4547(20000715)61:2<121::AID-JNR1>3.0.CO;2-4. View